tbuckley/cabot-search huggingface dataset:
Rural environment reduces allergic inflammation by modulating the gut microbiota
Authors: Zhaowei Yang, Zhong Chen, Xinliu Lin, Siyang Yao, Mo Xian, Xiaoping Ning, Wanyi Fu, Mei Jiang, Naijian Li, Xiaojun Xiao, Mulin Feng, Zexuan Lian, Wenqing Yang, Xia Ren, Zhenyu Zheng, Jiefeng Zhao, Nili Wei, Wenju Lu, Marjut Roponen, Bianca Schaub, Gary W. K. Wong, Zhong Su, Charles Wang, Jing Li
Journal: Gut Microbes (2022)

Rural environments and microbiota are linked to a reduction in the prevalence of allergies. However, the mechanism underlying the reduced allergies modulated by rural residency is unclear. Here, we assessed gut bacterial composition and metagenomics in urban and rural children in the EuroPrevall-INCO cohort. Airborne dusts, including mattress and rural henhouse dusts, were profiled for bacterial and fungal composition by amplicon sequencing. Mice were repeatedly exposed to intranasal dust extracts and evaluated for their effects on ovalbumin (OVA)-induced allergic airway inflammation, and gut microbiota restoration was validated by fecal microbiota transplant (FMT) from dust-exposed donor mice. We found that rural children had fewer allergies and unique gut microbiota with fewer Bacteroides and more Prevotella. Indoor dusts in rural environments harbored higher endotoxin level and diversity of bacteria and fungi, whereas indoor urban dusts were enriched with Aspergillus and contained elevated pathogenic bacteria. Intranasal administration of rural dusts before OVA sensitization reduced respiratory eosinophils and blood IgE level in mice and also led to a recovery of gut bacterial diversity and Ruminiclostridium in the mouse model. FMT restored the protective effect by reducing OVA-induced lung eosinophils in recipient mice. Together, these results support a cause-effect relationship between exposure to dust microbiota and allergy susceptibility in children and mice. Specifically, rural environmental exposure modulated the gut microbiota, which was essential in reducing allergy in children from Southern China. Our findings support the notion that the modulation of gut microbiota by exposure to rural indoor dust may improve allergy prevention.
Pathological collagen targeting and penetrating liposomes for idiopathic pulmonary fibrosis therapy
Authors: Ming-Yuan Yang, Yi-Jun Lin, Meng-Meng Han, Yu-Yang Bi, Xing-Yue He, Lei Xing, Jee-Heon Jeong, Tian-Jiao Zhou, Hu-Lin Jiang
Journal: Journal of Controlled Release (2022)
Public health opportunities resulting from sufficient HPV vaccine supply and a single-dose vaccination schedule
Authors: Aimée R Kreimer, Tania Cernuschi, Helen Rees, Julia M L Brotherton, Carolina Porras, John Schiller
Journal: JNCI Journal of the National Cancer Institute (2022)

Many countries with the highest burdens of cervical cancer have not yet offered human papillomavirus (HPV) vaccines to most of their age-eligible girls, who as adults also have limited or no access to effective cervical cancer screening or treatment. There are now 2 complementary developments that could make HPV vaccines more accessible and affordable: 1) the current and projected increases in HPV vaccine supply; and 2) the permissive recommendation for single-dose HPV vaccination schedules. This change in policy paired with the healthier HPV vaccine supply is an incredible opportunity to facilitate rapid access and expansion of HPV vaccination. Female adolescent vaccination including multiage cohorts must be prioritized. In the coming decades, this is the most cost-effective approach to avert millions of projected cervical cancer cases, which account for most HPV-related cancers globally.
Metabolic and Nonmetabolic Functions of PSAT1 Coordinate Signaling Cascades to Confer EGFR Inhibitor Resistance and Drive Progression in Lung Adenocarcinoma
Authors: Ming-Yu Luo, Ye Zhou, Wei-Ming Gu, Cheng Wang, Ning-Xiang Shen, Jiang-Kai Dong, Hui-Min Lei, Ya-Bin Tang, Qian Liang, Jing-Hua Zou, Lu Xu, Pengfei Ma, Guanglei Zhuang, Ling Bi, Ling Xu, Liang Zhu, Hong-Zhuan Chen, Ying Shen
Journal: Cancer Research (2022)

Emerging evidence demonstrates that the dysregulated metabolic enzymes can accelerate tumorigenesis and progression via both metabolic and nonmetabolic functions. Further elucidation of the role of metabolic enzymes in EGFR inhibitor resistance and metastasis, two of the leading causes of death in lung adenocarcinoma, could help improve patient outcomes. Here, we found that aberrant upregulation of phosphoserine aminotransferase 1 (PSAT1) confers erlotinib resistance and tumor metastasis in lung adenocarcinoma. Depletion of PSAT1 restored sensitivity to erlotinib and synergistically augmented the tumoricidal effect. Mechanistically, inhibition of PSAT1 activated the ROS-dependent JNK/c-Jun pathway to induce cell apoptosis. In addition, PSAT1 interacted with IQGAP1, subsequently activating STAT3-mediated cell migration independent of its metabolic activity. Clinical analyses showed that PSAT1 expression positively correlated with the progression of human lung adenocarcinoma. Collectively, these findings reveal the multifunctionality of PSAT1 in promoting tumor malignancy through its metabolic and nonmetabolic activities.Metabolic and nonmetabolic functions of PSAT1 confer EGFR inhibitor resistance and promote metastasis in lung adenocarcinoma, suggesting therapeutic targeting of PSAT1 may attenuate the malignant features of lung cancer.
Pharmacokinetics of intact lipid nanocapsules using new quantitative FRET technique
Authors: Vincent Lebreton, Norraseth Kaeokhamloed, Anastasiia Vasylaki, Grégory Hilairet, Adélie Mellinger, Jérôme Béjaud, Patrick Saulnier, Frédéric Lagarce, Florence Gattacceca, Samuel Legeay, Emilie Roger
Journal: Journal of Controlled Release (2022)
Mitotic Checkpoint Imbalances in Familial Cancer
Authors: Carolina Villarroya-Beltri, Marcos Malumbres
Journal: Cancer Research (2022)

Numerical chromosomal aberrations are highly frequent in cancer cells. However, tumor-associated mutations in regulators of the mitotic machinery that controls chromosome segregation are rather rare. By sequencing families with hereditary cancer, Chen and colleagues report two novel heterozygous mutations in CDC20, a coactivator of the anaphase-promoting complex (APC/C) and a target of the spindle assembly checkpoint (SAC) that prevents chromosome missegregation during mitosis. CDC20 mutations result in partial SAC functionality and segregate with tumor susceptibility in families with aneuploid ovarian cancers and other malignancies. The expression of these mutations in a knock-in mouse model accelerates the development of Myc-induced lymphomas and mortality, strongly supporting the notion that partial dysfunction of mitotic regulators may have profound implications in spontaneous and hereditary cancer. See related article by Chen et al., p. 3499.
Characterization of the enhanced infectivity and antibody evasion of Omicron BA.2.75
Authors: Yunlong Cao, Weiliang Song, Lei Wang, Pan Liu, Can Yue, Fanchong Jian, Yuanling Yu, Ayijiang Yisimayi, Peng Wang, Yao Wang, Qianhui Zhu, Jie Deng, Wangjun Fu, Lingling Yu, Na Zhang, Jing Wang, Tianhe Xiao, Ran An, Jing Wang, Lu Liu, Sijie Yang, Xiao Niu, Qingqing Gu, Fei Shao, Xiaohua Hao, Bo Meng, Ravindra Kumar Gupta, Ronghua Jin, Youchun Wang, Xiaoliang Sunney Xie, Xiangxi Wang
Journal: Cell Host & Microbe (2022)

Recently emerged SARS-CoV-2 Omicron subvariant, BA.2.75, displayed a growth advantage over circulating BA.2.38, BA.2.76, and BA.5 in India. However, the underlying mechanisms for enhanced infectivity, especially compared with BA.5, remain unclear. Here, we show that BA.2.75 exhibits substantially higher affinity for host receptor angiotensin-converting enzyme 2 (ACE2) than BA.5 and other variants. Structural analyses of BA.2.75 spike shows its decreased thermostability and increased frequency of the receptor binding domain (RBD) in the "up" conformation under acidic conditions, suggesting enhanced low-pH-endosomal cell entry. Relative to BA.4/BA.5, BA.2.75 exhibits reduced evasion of humoral immunity from BA.1/BA.2 breakthrough-infection convalescent plasma but greater evasion of Delta breakthrough-infection convalescent plasma. BA.5 breakthrough-infection plasma also exhibits weaker neutralization against BA.2.75 than BA.5, mainly due to BA.2.75's distinct neutralizing antibody (NAb) escape pattern. Antibody therapeutics Evusheld and Bebtelovimab remain effective against BA.2.75. These results suggest BA.2.75 may prevail after BA.4/BA.5, and its increased receptor-binding capability could support further immune-evasive mutations.
Retraction Note: EGFR and MET receptor tyrosine kinase–altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers
Authors: Michela Garofalo, Giulia Romano, Gianpiero Di Leva, Gerard Nuovo, Young-Jun Jeon, Apollinaire Ngankeu, Jin Sun, Francesca Lovat, Hansjuerg Alder, Gerolama Condorelli, Jeffrey A. Engelman, Mayumi Ono, Jin Kyung Rho, Luciano Cascione, Stefano Volinia, Kenneth P. Nephew, Carlo M. Croce
Journal: Nature Medicine (2022)
Memory CD4+ T cells that co-express PD1 and CTLA4 have reduced response to activating stimuli facilitating HIV latency
Authors: Thomas A. Rasmussen, Jennifer M. Zerbato, Ajantha Rhodes, Carolin Tumpach, Ashanti Dantanarayana, James H. McMahon, Jillian S.Y. Lau, J. Judy Chang, Celine Gubser, Wendy Brown, Rebecca Hoh, Melissa Krone, Rachel Pascoe, Chris Y. Chiu, Michael Bramhall, Hyun Jae Lee, Ashraful Haque, Rèmi Fromentin, Nicolas Chomont, Jeffrey Milush, Renee M. Van der Sluis, Sarah Palmer, Steven G. Deeks, Paul U. Cameron, Vanessa Evans, Sharon R. Lewin
Journal: Cell Reports Medicine (2022)

Programmed cell death 1 (PD1) and cytotoxic T lymphocyte-associated protein 4 (CTLA4) suppress CD4+ T cell activation and may promote latent HIV infection. By performing leukapheresis (n = 21) and lymph node biopsies (n = 8) in people with HIV on antiretroviral therapy (ART) and sorting memory CD4+ T cells into subsets based on PD1/CTLA4 expression, we investigate the role of PD1 and CTLA 4 in HIV persistence. We show that double-positive (PD1+CTLA4+) cells in blood contain more HIV DNA compared with double-negative (PD1-CTLA4-) cells but still have a lower proportion of cells producing multiply spliced HIV RNA after stimulation as well as reduced upregulation of T cell activation and proliferation markers. Transcriptomics analyses identify differential expression of key genes regulating T cell activation and proliferation with MAF, KLRB1, and TIGIT being upregulated in double-positive compared with double-negative cells, whereas FOS is downregulated. We conclude that, in addition to being enriched for HIV DNA, double-positive cells are characterized by negative signaling and a reduced capacity to respond to stimulation, favoring HIV latency.
How to improve discussions about osteoarthritis in primary care
Authors: Helen Saul, Deniz Gursul, Brendan Deeney, Jane Vennik
Journal: BMJ (2022)

The studyVennik J, Hughes S, Smith KA, et al. Patient and practitioner priorities and concerns about primary healthcare interactions for osteoarthritis: a meta-ethnography. Patient Educ Couns 2022;105:1865-77.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/discussions-about-osteoarthritis-in-primary-care/.
Why I . . . play table tennis
Authors: Kathy Oxtoby
Journal: BMJ (2022)

<h3>Background and purpose</h3> Coincidental aneurysms in the target vessels of stroke patients with large vessel occlusions (LVO) may pose risks during endovascular mechanical thrombectomy (MTE), but there are almost no data on this subject. Motivated by an incident of rupture of a hidden aneurysm induced by withdrawal of a stent retriever during a MTE procedure, this study examines the prevalence of aneurysms, associated complications, and implications for treatment strategies in patients with LVO stroke. <h3>Methods</h3> A single-center retrospective analysis of angiographic and CT/MRI images and case records of 300 consecutive patients with LVO stroke treated with MTE was performed. <h3>Results</h3> Aneurysms related to target vessels were detected in 11/300 patients, in 10/11 in the anterior circulation. In 9/11 patients the aneurysms were unknown prior to the stroke. The observed prevalence was &gt;2-fold higher than expected for a healthy reference population. There was one complication (aneurysm rupture), as described above. In two subsequent patients with known aneurysms, MTE was conducted mainly with aspiration techniques which failed, contributing to a low recanalization rate in patients with aneurysm (45%). <h3>Conclusions</h3> The prevalence of aneurysms is relatively high in patients with LVO stroke, particularly in older, female, hypertensive patients, presumably reflecting overlapping risk factors. MTE should not be withheld from patients with LVO stroke with aneurysms, but particularly cautious approaches may be warranted. Further research in larger samples is required to obtain precise data on the prevalence and associated complication rates in MTE procedures. This is necessary to estimate the true risk and to tailor endovascular strategies in these patients.
Association between initiation of fluoroquinolones and hospital admission or emergency department visit for suicidality: population based cohort study
Authors: Junyi Wang, Joshua J Gagne, Sushama Kattinakere-Sreedhara, Michael A Fischer, Katsiaryna Bykov
Journal: BMJ (2022)

To evaluate the association between initiation of fluoroquinolones and hospital admission or emergency department visit for suicidality. Population based cohort study. IBM MarketScan database, USA. 2 756 268 adults (≥18 years) who initiated an oral fluoroquinolone (ciprofloxacin, levofloxacin, moxifloxacin, gemifloxacin, ofloxacin, gatifloxacin, norfloxacin, lomefloxacin, besifloxacin) or comparator antibiotic (January 2003 to September 2015) and had at least six months of continuous health plan enrollment and a diagnosis of pneumonia or urinary tract infection (UTI) three days or less before the drug initiation date. Comparator antibiotics were azithromycin in the pneumonia cohort and trimethoprim-sulfamethoxazole in the UTI cohort. Participants were matched 1:1 within each cohort on a propensity score, calculated from a multivariable logistic regression model that included 57 baseline covariates. Primary outcome was hospital admission or emergency department visit for suicidal ideation or self-harm within 60 days after treatment initiation. Cox proportional hazard models were used to estimate hazard ratios and 95% confidence intervals. The pneumonia cohort included 551 042 individuals, and the UTI cohort included 2 205 526 individuals. During the 60 day follow-up, 181 events were observed in the pneumonia cohort and 966 in the UTI cohort. The adjusted hazard ratios for fluoroquinolones were 1.01 (95% confidence interval 0.76 to 1.36) versus azithromycin in the pneumonia cohort and 1.03 (0.91 to 1.17) versus trimethoprim-sulfamethoxazole in the UTI cohort. Results were consistent across sensitivity analyses and subgroups of sex, age, or history of mental illnesses. Initiation of fluoroquinolones was not associated with a substantially increased risk of admission to hospital or emergency department visits for suicidality compared with azithromycin or trimethoprim-sulfamethoxazole.
Correction to: Mutant SETBP1 enhances NRAS-driven MAPK pathway activation to promote aggressive leukemia
Authors: Sarah A. Carratt, Theodore P. Braun, Cody Coblentz, Zachary Schonrock, Rowan Callahan, Brittany M. Curtiss, Lauren Maloney, Amy C. Foley, Julia E. Maxson
Journal: Leukemia (2022)
Reply to Yongbao Wei, Haijian Huang, and Liefu Ye’s Letter to the Editor re: George J. Netto, Mahul B. Amin, Daniel M. Berney, et al. The 2022 World Health Organization Classification of Tumors of the Urinary System and Male Genital Organs—Part B: Prostate and Urinary Tract Tumors. Eur Urol. 2022;82:469–82.
Authors: Mark A. Rubin, Mahul B. Amin, Eva Compérat, Anthony Gill, Arndt Hartman, Santosh Menon, Maria Raspollini, John Srigley, Puay Hoon Tan, Satish Ticktoo, Toyonori Tsuzuki, Samra Turajlic, Ian Cree, Daniel Berney, Holger Moch, George J. Netto
Journal: European Urology (2022)
Prostate Adenocarcinoma Grade Group 1: Rationale for Retaining a Cancer Label in the 2022 World Health Organization Classification
Authors: George J. Netto, Mahul B. Amin, Eva M. Compérat, Anthony J. Gill, Arndt Hartmann, Holger Moch, Santosh Menon, Maria R. Raspollini, Mark A. Rubin, John R. Srigley, Puay Hoon Tan, Satish K. Tickoo, Toyonori Tsuzuki, Samra Turajlic, Ian Cree, Daniel M. Berney
Journal: European Urology (2022)
Reply to Hela Sassi, Olivier Caron, and Etienne Rouleau’s Letter to the Editor re: Kara N. Maxwell, Heather H. Cheng, Jacquelyn Powers, et al. Inherited TP53 Variants and Risk of Prostate Cancer. Eur Urol 2022;81:243–50
Authors: Kara N. Maxwell, Colin C. Pritchard
Journal: European Urology (2022)
Association of <scp>time‐to‐intravenous</scp> furosemide with mortality in acute heart failure: data from <scp>REPORT‐HF</scp>
Authors: Wouter Ouwerkerk, Jasper Tromp, John G.F. Cleland, Christiane E. Angermann, Ulf Dahlstrom, Georg Ertl, Mahmoud Hassanein, Sergio V. Perrone, Mathieu Ghadanfar, Anja Schweizer, Achim Obergfell, Kenneth Dickstein, Gerasimos Filippatos, Sean P. Collins, Carolyn S.P. Lam
Journal: European Journal of Heart Failure (2022)

Acute heart failure can be a life-threatening medical condition. Delaying administration of intravenous furosemide (time-to-diuretics) has been postulated to increase mortality, but prior reports have been inconclusive. We aimed to evaluate the association between time-to-diuretics and mortality in the international REPORT-HF registry.We assessed the association of time-to-diuretics within the first 24 h with in-hospital and 30-day post-discharge mortality in 15 078 patients from seven world regions in the REPORT-HF registry. We further tested for effect modification by baseline mortality risk (ADHERE risk score), left ventricular ejection fraction (LVEF) and region. The median time-to-diuretics was 67 (25th-75th percentiles 17-190) min. Women, patients with more signs and symptoms of heart failure, and patients from Eastern Europe or Southeast Asia had shorter time-to-diuretics. There was no significant association between time-to-diuretics and in-hospital mortality (p > 0.1). The 30-day mortality risk increased linearly with longer time-to-diuretics (administered between hospital arrival and 8 h post-hospital arrival) (p = 0.016). This increase was more significant in patients with a higher ADHERE risk score (pinteraction = 0.008), and not modified by LVEF or geographic region (pinteraction > 0.1 for both).In REPORT-HF, longer time-to-diuretics was not associated with higher in-hospital mortality. However, we did found an association with increased 30-day mortality, particularly in high-risk patients, and irrespective of LVEF or geographic region.ClinicalTrials.gov Identifier NCT02595814.
Association of epicardial adipose tissue with proteomics, coronary flow reserve, cardiac structure and function, and quality of life in heart failure with preserved ejection fraction: insights from the <scp>PROMIS‐HFpEF</scp> study
Authors: Ashwin Venkateshvaran, Ulrika Ljung Faxen, Camilla Hage, Erik Michaëlsson, Sara Svedlund, Antti Saraste, Lauren Beussink‐Nelson, Maria Lagerstrom Fermer, Li‐Ming Gan, Jasper Tromp, Carolyn S.P. Lam, Sanjiv J. Shah, Lars H. Lund
Journal: European Journal of Heart Failure (2022)

ABSTRACT Aim Epicardial adipose tissue (EAT) may play a role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). We investigated associations of EAT with proteomics, coronary flow reserve (CFR), cardiac structure and function, and quality of life (QoL) in the prospective multinational PROMIS‐HFpEF cohort. Methods and results Epicardial adipose tissue was measured by echocardiography in 182 patients and defined as increased if ≥9 mm. Proteins were measured using high‐throughput proximity extension assays. Microvascular dysfunction was evaluated with Doppler‐based CFR, cardiac structural and functional indices with echocardiography and QoL by Kansas City Cardiomyopathy Questionnaire (KCCQ). Patients with increased EAT ( n = 54; 30%) had higher body mass index (32 [28–40] vs. 27 [23–30] kg/m 2 ; p &lt; 0.001), lower N‐terminal pro‐B‐type natriuretic peptide (466 [193–1133] vs. 1120 [494–1990] pg/ml; p &lt; 0.001), smaller indexed left ventricular (LV) end‐diastolic and left atrial (LA) volumes and tendency to lower KCCQ score. Non‐indexed LV/LA volumes did not differ between groups. When adjusted for body mass index, EAT remained associated with LV septal wall thickness (coefficient 1.02, 95% confidence interval [CI] 1.00–1.04; p = 0.018) and mitral E wave deceleration time (coefficient 1.03, 95% CI 1.01–1.05; p = 0.005). Increased EAT was associated with proteomic markers of adipose biology and inflammation, insulin resistance, endothelial dysfunction, and dyslipidaemia but not significantly with CFR. Conclusion Increased EAT was associated with cardiac structural alterations and proteins expressing adiposity, inflammation, lower insulin sensitivity and endothelial dysfunction related to HFpEF pathology, probably driven by general obesity. Potential local mechanical or paracrine effects mediated by EAT remain to be elucidated.
Genome-wide association and Mendelian randomization study of fibroblast growth factor 21 reveals causal associations with hyperlipidemia and possibly NASH
Authors: Susanna C. Larsson, Karl Michaëlsson, Marina Mola-Caminal, Jonas Höijer, Christos S. Mantzoros
Journal: Metabolism (2022)

BackgroundFibroblast growth factor 21 (FGF21) is a hepatokine that produces metabolic benefits, such as improvements of lipid profile. We performed a genome-wide association study (GWAS) to identify genetic variants associated with circulating FGF21 and investigated the causal effects of FGF21 on pertinent outcomes using Mendelian randomization (MR).MethodsWe conducted a GWAS testing ∼7.8 million DNA sequence variants with circulating FGF21 in a discovery cohort of 6259 Swedish adults with replication in 4483 Swedish women. We then performed two-sample MR analyses of genetically predicted circulating FGF21 in relation to alcohol and nutrient intake, cardiovascular and metabolic biomarkers and diseases, and liver function biomarkers using publicly available GWAS summary statistics data.ResultsOur GWAS identified multiple single-nucleotide polymorphisms with genome-wide significant associations (P < 5 × 10−8) with circulating FGF21 on chromosomes 2 and 19 in or near the GCKR and FGF21 genes, respectively. The strongest signal at the FGF21 locus (rs2548957, β = 0.181, P < 2.18 × 10−42) displayed in two-sample MR analyses robust associations with lower alcohol intake, lower circulating low-density lipoprotein cholesterol, apolipoprotein B, C-reactive protein, gamma-glutamyl transferase, and galectin-3 concentrations, and higher circulating insulin-like growth factor-I and alkaline phosphatase concentrations after correcting for multiple testing (P < 0.0018) whereas associations with fat mass, type 2 diabetes, and cardiovascular disease were largely null.ConclusionsWe identified robust associations of certain genetic variants in or near the GCKR and FGF21 genes with circulating FGF21 concentrations. Furthermore, our results support a strong causal effect of FGF21 on improved lipid profile, reduced alcohol consumption and C-reactive protein concentrations, and liver function biomarkers including fibrosis. We found largely null or weak positive associations with fat mass, diabetes, and cardiovascular disease as well as higher insulin-like growth factor-I concentrations, which could indicate a compensatory increase to regulate the above FGF21 resistant states in humans.